Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS). A great deal of our understanding about the immunologic processes that underlie MS derives from studies in its autoimmune animal model, experimental autoimmune encephalomyelitis (EAE). However, the vast majority of studies in EAE and MS have focused on evaluating and targeting CD4+ T cell responses, with the general assumption that these diseases are predominantly Th1/Th17-mediated and Th2/Treg-modulated. Recent reports from others and us indicate that CD8+ T cells may play an important role in the pathogenesis as well as regulation of autoimmune demyelination. The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. While it is known that CD8+ T cells represent the predominant T cell in an MS lesion and are oligoclonally expanded at the site of pathology, the antigenic specificity of these cells and their role is not known. There is high prevalence of CNS-specific CD8+ T cells in MS patients as well as multiple models of EAE. While it makes intuitive sense that a CNS-targeted, MHC Class I-restricted CD8+ T cell response would likely have a pathogenic role in disease, our recent studies have generated the first evidence for a novel and unexpected immune suppressor role for neuroantigen-specific CD8+ T cells in EAE. We thus hypothesize that CNS-specific CD8+ T cells form an important arm of intrinsic immune regulation during autoimmune demyelinating disease. We propose that this natural process can be harnessed for the development of an effective immunotherapeutic strategy. The experiments proposed in this application will directly address the mechanisms of immune modulation by CNS-reactive CD8+ T cells, delineating their cellular, molecular and trafficking requirements. Moreover, the most potent immune suppressive subset of this population will be defined with the goal of developing a novel immunotherapeutic approach. We believe that the proposed experiments will provide greater fundamental insight into CD8+ T cell-mediated immune regulation during health and disease and will pave the way for newer intervention strategies for this and other immune-mediated diseases.